One of the strategies utilized by VV to evade the host immune surveillance is inhibition of dendritic cell (DC) maturation. DC maturation is defined functionally as the acquisition of potent xmmunogenic capacity. This includes up-regulation of surface MHC class I and class II molecules, as well as CD40, CD80, and CD86, which mediate efficient antigen presentation and stimulation of naive T cells. Mature dendritic cells (mDCs) also produce cytokines and chemokines and are responsible for directing T cells to a defined differentiation pathway, which in turn evokes a specific immune response. Although the significance of dendritic ceils (DCs) for a proper immune response is clear, very little is known regarding how W infection affects DC functions and host immune responses. We hypothesize that VV infection induces irreversible events in ammature DCs, which paralyze VV-infected DCs to respond to a maturation signal, resulting in the loss of VV-specific immunity, in a host. Therefore, the goal of this project is to test this hypothesis by investigating the underlying mechanisms of how VV modulates DC-mediated immune responses. VV has been used as a vaccine for smallpox, and widely used as a vehicle to introduce a foreign gene to cells. If VV inhibits DC maturation, however, the usage of VV as a vaccine needs to be re-evaluated. A better understanding of DC maturation at a molecular level in the context of VV infection is crucial and required to design better strategies to prevent the loss of life and complications associated with viruses such as smallpox, which is the ultimate goal of the Program Project.